Process for preparing a novel phenicol antibacterial agent

Abstract

The present invention provides a novel process for preparing a diastereomeric mixture of the phenicol of Formula (1), its use for the treatment of bacterial infections in animals, and veterinary compositions containing the Formula (1) compound, diastereomers thereof, and veterinary acceptable salts thereof.

1 . A process for preparing the Formula (1) compound, 
       
         
           
           
               
               
           
         
       
       comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst in the presence of an alcohol, a ligand, and a borylation buffer; 
 
       
         
           
           
               
               
           
         
         b) borylating the preactivated Formula (B) compound of Step (a) by adding a borylating agent in an alcohol; 
         c) mixing the Formula (A) compound with a base in an alcohol, co-solvent, or mixtures thereof; and 
       
       
         
           
           
               
               
           
         
         d) adding the reactants of Step (c) to the reactants of Step (b) to give the compound of Formula (1), and diastereomers thereof. 
       
     
     
         2 . The process of  claim 1  comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst selected from the group consisting of Pd(OAc) 2 , PdCl 2 , Pd-G2-XPhos, Pd-XPhos Crotyl Cl, Pd(dppf)Cl 2 , Pd-G2-PCy 3 , and Pd 2 (dba) 3 , in the presence of an alcohol, a ligand selected from the group consisting of XPhos, SPhos, dppp, dppf, dba, PPh 3 , and PCy 3 , and a borylation buffer that comprises an acid and a base, wherein said acid is selected from the group consisting of HOAc, citric acid, formic acid, chloroacetic acid, and ammonium acetate; 
 b) borylating the preactivated Formula (B) compound of step (a) by adding a borylating agent in an alcohol; wherein the borylating agent is selected from the group consisting of bisboronic acid, bisboronic acid and ethylene glycol, bisboronic acid and propylene glycol, B 2 Pin 2 , and B 2 (NMe 2 ) 4 ; 
 c) mixing the Formula (A) compound with a base in an alcohol, co-solvent, or mixtures thereof; and 
 d) mixing the reactants of Step (c) to the reactants of Step (b) to give the compound of Formula (1), and diastereomers thereof. 
 
     
     
         3 . The process of  claim 1 , wherein the base in Step (a) and (c) is selected from the group consisting of KOAc, CsOAc, TEA, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , DIPEA, and K 3 PO 4 , and mixtures thereof; and wherein the alcohol in Steps (a), (b), and (c) is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and 2-butanol. 
     
     
         4 . The process of  claim 3 , wherein the alcohol in Steps (a) and (b) is anhydrous ethanol and the alcohol in Step (c) is aqueous ethanol. 
     
     
         5 . The process of  claim 1 , wherein the co-solvent of Step (c) is selected from the group consisting of iPrOAc, EtOAc, DMF, DME, THF, MeTHF, acetonitrile, and mixtures thereof. 
     
     
         6 . The process of  claim 1  comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst that is Pd(OAc) 2  in the presence of anhydrous ethanol, a ligand that is XPhos, and a borylation buffer comprising the acid, HOAc, and the base, KOAc; 
 b) borylating the preactivated Formula (B) compound of Step (a) by adding the borylating agent bisboronic acid and ethylene glycol in anhydrous ethanol; 
 c) mixing the Formula (A) compound with a K 2 CO 3  or Na 2 CO 3  in aqueous THF; and 
 d) mixing the reactants of Step (c) to the reactants of Step (b) to give the compound of Formula (1), and diastereomers thereof; and wherein solutions added to the reaction in Steps (a-c) are purged with N 2  or Ar and the reactions in Steps (a-d) occur under an inert atmosphere of N 2  or Ar. 
 
     
     
         7 . A process for preparing the Formula (1) compound, 
       
         
           
           
               
               
           
         
       
       comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst in the presence of an alcohol, ligand, and a borylation buffer; 
 
       
         
           
           
               
               
           
         
         b) borylating the preactivated Formula (B) compound of Step (a) by adding a borylating agent in an alcohol to the reactants of Step (a); 
         c) mixing the Formula (A) compound with a base in an alcohol, co-solvent, or mixtures thereof; 
       
       
         
           
           
               
               
           
         
         d) adding the reactants of Step (c) to the reactants of Step (b) to give the Formula (1) compound, and diastereomers thereof; 
         e) purifying the Formula (1) compound of Step (d) by concentrating the reaction product of Step (d) and extracting the Formula (1) compound into an extracting solvent; 
         f) adding an aqueous wash to the extracting solvent of Step (e), stirring the extraction and wash and separating the organic layer; 
         g) adding a palladium scavenger to the organic layer of Step (f) or recycling the organic layer of step (f) through a cartridge of metal scavenger, stirring and filtering out the solids, rinsing the solids with an extraction solvent(s) and concentrating the filtrate; 
         h) dissolving the resultant concentrate of Step (g) in an organic solvent(s) with heat, cooling and seeding the mixture with the Formula (1) compound; 
         i) cooling the mixture of step (h), adding an optional anti-solvent, collecting the resultant solids by filtration, rinsing the solids with an anti-solvent, and then drying the solids to prepare a 1:1 diastereomeric mixture of the Formula (1) compound. 
       
     
     
         8 . The process of  claim 7  comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst selected from the group consisting of Pd(OAc) 2 , PdCl 2 , Pd-G2-XPhos, Pd-XPhos Crotyl Cl, Pd(dppf)Cl 2 , Pd-G2-PCy 3 , and Pd 2 (dba) 3 , in the presence of an alcohol, a ligand selected from the group consisting of XPhos, SPhos, dppp, dppf, dba, PPh 3 , and PCy 3 , and a borylation buffer that comprises an acid and a base, wherein said acid is selected from the group consisting of HOAc, citric acid, formic acid, chloroacetic acid, and ammonium acetate; 
 b) borylating the preactivated Formula (B) compound of Step (a) by adding a borylating agent selected from the group consisting of bisboronic acid, bisboronic acid and ethylene glycol; bisboronic acid and propylene glycol; B 2 Pin 2 , and B 2 (NMe 2 ) 4  in an alcohol; 
 c) mixing the Formula (A) compound with a base in an alcohol, co-solvent, or mixtures thereof; and wherein the base in Step (a) and (c) is selected from the group consisting of KOAc, CsOAc, TEA, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , DIPEA, and K 3 PO 4 ; and wherein the alcohol in Steps (a) and (B) in anhydrous ethanol; 
 d) mixing the reactants of Step (c) to the reactants of Step (b) to give the compound of Formula (1), and diastereomers thereof; 
 e) purifying the Formula (1) compound of Step (d) by concentrating the reaction product of Step (d) and extracting the Formula (1) compound into an extracting solvent selected from the group consisting of THF, EtOAc, MeOAc, methylene chloride and MeTHF; 
 f) adding an aqueous wash to the extraction of step (e) selected from water or brine, each of which contain a palladium chelator selected from the group consisting of EDA, TMT-Na 3 , NH 4 OH, TMT, NaHSO 3 , thiourea, DEA, EDTA, Ac-L-cysteine, citric acid and mixtures thereof, and separating the organic layer. 
 g) adding a palladium scavenger to the organic layer of step (f), or recycling the organic layer of step (f) through a cartridge of metal scavenger selected from the group consisting of Carbon with EDA, Silica gel with EDA, Si-Thiol, MP-TU, MP-TMT, Si-TMT, Si-DMT, and Si-cysteine, filtering out the solids, rinsing the solids with an extraction solvent(s) and concentrating the filtrate; 
 h) dissolving the resulting concentrate of Step (g) in an organic solvent selected from the group consisting of MEK, iPrOAc, EtOAc, acetone, 1-butanol, 1-propanol, 2-propanol, and mixtures thereof with heat; cooling and seeding the solution with the Formula (1) compound; and 
 i) cooling the mixture of step (h), optionally adding an anti-solvent selected from the group consisting of water, MTBE, hexane, heptane, and mixtures thereof; collecting the resultant solids by filtration, rinsing the solids with the anti-solvent, and then drying the solids to prepare a 1:1 diastereomeric mixture of the Formula (1) compound. 
 
     
     
         9 . The process of  claim 8 , wherein the co-solvent is selected from the group consisting of iPrOAc, EtOAc, DMF, DME, THF, MeTHF, and acetonitrile, and mixtures thereof; and wherein the palladium catalyst in Step (a) is Pd(OAc) 2 ; and wherein the ligand in Step (a) is XPhos and the borylation buffer in Step (a) is an alcohol solution comprising HOAc and a base; and wherein the borylating agent in Step (b) is bisboronic acid and ethylene glycol in anhydrous ethanol. 
     
     
         10 . The process of  claim 9 , wherein the base in Step (a) is KOAc and the base in Step (c) is selected from the group consisting of K 2 CO 3 , Na 2 CO 3 , TEA, and mixtures thereof. 
     
     
         11 . The process of  claim 10 , wherein the extracting solvent in Step (e) is THF; and wherein the organics from Step (e) are washed 1×, 2×, 3×, or 4× with the aqueous wash; and wherein the palladium scavenger in Step (g) is Carbon with EDA and the organic solvent is selected from the group consisting of MEK, IPA, EtOAc, acetone, 1-butanol, 1-propanol, 2-propanol, and mixtures thereof; and wherein the anti-solvent in Step (h) is selected from the group selected from water, MTBE, hexane, heptane, and mixtures thereof; and the solutions added to the reaction in Steps (a-c) are purged with N 2  or Ar and the reaction in Steps (a-d) occurs under a N 2  or Ar atmosphere. 
     
     
         12 . The process of  claim 11  wherein the organic solvent is MEK, 1-propanol, or a mixture thereof; and the anti-solvent is heptane. 
     
     
         13 . A process for preparing the Formula (1) compound, 
       
         
           
           
               
               
           
         
       
       comprising the steps of:
 a) pre-activating the Formula (B) compound with a palladium catalyst selected from the group consisting of Pd(OAc) 2 , PdCl 2 , Pd-G2-XPhos, Pd-XPhos Crotyl Cl, Pd(dppf)Cl 2 , Pd-G2-PCy 3 , and Pd 2 (dba) 3 ; in the presence of an alcohol, a ligand selected from the group consisting of XPhos, SPhos, dppp, dppf, dba, PPh 3 , and PCy 3 ; and a borylation buffer; 
 
       
         
           
           
               
               
           
         
         b) borylating the preactivated Formula (B) compound of Step (a) by adding a borylating agent selected from the group consisting of bisboronic acid, bisboronic acid and ethylene glycol; bisboronic acid and propylene glycol; B 2 Pin 2 , and B 2 (NMe 2 ) 4  in an alcohol; 
         c) mixing the Formula (A) compound with a base in an alcohol, co-solvent, or mixtures thereof; 
       
       
         
           
           
               
               
           
         
         d) adding the reactants of Step (c) to the reactants of Step (b) to give the Formula (1) compound, and diastereomers thereof. 
       
     
     
         14 . The process of  claim 13 , wherein the borylation buffer in step (a) comprises an acid and a base, wherein the acid is selected from the group consisting of HOAc, citric acid, formic acid, chloroacetic acid, and ammonium acetate; and the base is selected from the group consisting of KOAc, CsOAc, TEA, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , DIPEA, and K 3 PO 4 . 
     
     
         15 . The process of  claim 14 , wherein the alcohol is anhydrous ethanol and the base in step (a) is KOAc and the base in step (c) is selected from the group consisting of K 2 CO 3 , Na 2 CO 3 , TEA, and mixtures thereof; and wherein the resultant Formula (1) compound is concentrated. 
     
     
         16 . The process of  claim 15 , wherein the Formula (1) compound is purified by extracting the compound into an extracting solvent selected from the group consisting of THF, EtOAc, MeOAc, methylene chloride and MeTHF. 
     
     
         17 . The process of  claim 16 , wherein the purified Formula (1) compound is washed with an aqueous wash of water or brine each of which contain a palladium chelator selected from the group consisting of EDA, TMT-Na 3 , NH 4 OH, TMT, NaHSO 3 , thiourea, DEA, EDTA, Ac-L-cysteine, citric acid and mixtures thereof, and separating the organic layer. 
     
     
         18 . The process of  claim 17 , further comprising the addition of a palladium scavenger that is Carbon with EDA to the organic layer or recycling the organic layer through a metal scavenger cartridge consisting of Carbon with EDA, Silica gel with EDA, Si-Thiol, MP-TU, MP-TMT, Si-TMT, Si-DMT, and Si-cysteine; filtering out the solids, rinsing the solids with an extraction solvent(s) and concentrating the filtrate. 
     
     
         19 . The process of  claim 18 , wherein the concentrated filtrate is dissolved in an organic solvent selected from the group consisting of MEK, iPrOAc, EtOAc, acetone, 1-butanol, 1-propanol, 2-propanol, and mixtures thereof with heat; cooling and seeding the solution with the Formula (1) compound. 
     
     
         20 . The process of  claim 19 , wherein the resulting mixture is cooled and optionally further comprising the addition of an anti-solvent selected from the group conbsisting of water, MTBE, hexane, heptane, and mixtures thereof; collecting the resultant solids by filtration, rinsing the solids with the anti-solvent, and then drying the solids to prepare a 1:1 diastereomeric mixture of the Formula (1) compound.